DESCRIPTION: The long-term goal of this application is to investigate the role of p53 in osteoblast differentiation, a process central to bone formation. Toward this goal, studies are proposed aimed at clarifying when and how p53 might function in this pathway. The role of p53 in the regulation of osteocalcin gene expression and other genes involved in bone differentiation will be investigated. The role of mdm-2, a downstream effector of p53, in osteocalcin gene regulation will be studied. Alterations in p53 expression and transactivation activity will be followed during in vitro bone differentiation to determine the stage and time at which induction of mdm-2 may result in osteocalcin expression. Other studies will address the question of whether p53-independent mdm-2 forms can function in this regulation, in the absence of p53. The applicant will also determine if p53 modulates the activity of the Insulin Like Growth Factor Binding Protein-3 and Bone Morphogenetic Protein-2 expression, during bone differentiation. Wherever possible the studies will be substantiated using osteoblasts from p53 heterozygous transgenic mice. The proposed studies are aimed at increasing our understanding of: 1) the exact mechanism of action of p53 in bone differentiation and osteocalcin gene regulation: 2) the role of mdm-2 as a transcriptional activator; 3) and the mechanisms by which p53 and mdm-2 genes may mediate bone maturation.